Effects of Fibrates on Metabolism of Statins in Human Hepatocytes

Abstract

ABSTRACT:This study investigated the metabolic interaction between fibrates and statin hydroxy acids in human hepatocytes. Gemfibrozil (GFZ) modestly affected the formation of ␤-oxidative products and CYP3A4-mediated oxidative metabolites of simvastatin hydroxy acid (SVA) but markedly inhibited the glucuronidation-mediated lactonization of SVA and the glucuronidation of a ␤-oxidation product (IC 50 ϳ50 and 15 M, respectively). In contrast, fenofibrate had a minimal effect on all the metabolic pathways of SVA. GFZ also significantly inhibited (IC 50 ϳ50-60 M) the oxidation of cerivastatin (CVA) and rosuvastatin (RVA), but not of atorvastatin (AVA), while effectively decreasing (IC 50 ϳ30 to 60 M) the lactonization of all three statins. As was observed previously with other statin hydroxy acids, RVA underwent significant glucuronidation to form an acyl glucuronide conjugate and lactonization to form RVA lactone in human liver microsomes and by UGT 1A1 and 1A3. While GFZ is not an inhibitor of CYP3A4, it is a competitive inhibitor (K i ‫؍‬ 87 M) of CYP2C8, a major catalyzing enzyme for CVA oxidation. These results suggest that 1) the pharmacokinetic interaction observed between GFZ and statins was not likely mediated by the inhibitory effect of GFZ on the ␤-oxidation, but rather by its effect primarily on the glucuronidation and non-CYP3A-mediated oxidation of statin hydroxy acids, and 2) there is a potential difference between fibrates in their ability to affect the pharmacokinetics of statins, and among statins in their susceptibility to metabolic interactions with GFZ in humans.Fibrates, lipid-regulating agents, and hydroxymethylglutaryl-coenzyme A reductase inhibitors or so called "statins", cholesterol lowering agents, are frequently prescribed together to treat patients with mixed hyperlipidemia (Shek and Ferrill, 2001). There have been reports of increased risk of myopathy, including rhabdomyolysis with this coadministration (Murdock et al., 1999). Despite being generally accepted as a class effect for all fibrate-statin combinations, this increased risk has been observed at varied incidences with different fibrates and statins. More documented cases for myopathy have been reported with gemfibrozil (GFZ 1 )-statin combined therapy than with other fibrate-statin combinations (Shek and Ferrill, 2001). Recently, cerivastatin (CVA) was withdrawn from the market due to disproportionate numbers of fatal rhabdomyolysis cases (compared with other marketed statins), many of which occurred in patients receiving concomitant GFZ (Farmer, 2001).Although it has generally been accepted that the increased risk of myopathy is due primarily to a pharmacodynamic drug-drug interaction, recent studies have suggested that the increased risk might also have a pharmacokinetic origin. In recent clinical studies, increases in the exposure mainly to statin hydroxy acids, but minimally to the lactone form of statins, were observed following coadministration of GFZ and statins (Backman et al., 2000;Kyrklund et al., 2001). Subsequently, ...

Therapeutic Roles of Peroxisome Proliferator–Activated Receptor Agonists

“…However, a statin/fibrate, particularly gemfibrozil, combination may be associated with increased risk of rhabdomyolysis. In vitro studies have highlighted that gemfibrozil may increase the myotoxic effects of statins (13,14) and that use of gemfibrozil results in higher plasma concentrations of statins (15)(16)(17)(18). Possible mechanisms for this include inhibition of statin glucuronidation (13), which may then reduce statin elimination in vivo.…”

“…In vitro studies have highlighted that gemfibrozil may increase the myotoxic effects of statins (13,14) and that use of gemfibrozil results in higher plasma concentrations of statins (15)(16)(17)(18). Possible mechanisms for this include inhibition of statin glucuronidation (13), which may then reduce statin elimination in vivo. Inhibition of the P450 enzyme CYP2C8 by gemfibrozil (13,19) may also impede elimination of statins (13).…”

Update on Statins: 2003

“…Fenofibrate does not appear to interfere with the UGT1A1 and UGT1A3 enzymes that mediate statin glucuronidation (fenofibrate is glucuronidated by UGT1A9 and UGT2B7). 21 Perhaps statinfenofibrate combinations may have less risk for interactions than therapy with statins and gemfibrozil. Other variables that may increase the likelihood of side effects with statins include advanced age, small body size, female gender, renal and hepatic dysfunction, perioperative periods, hypothyroidism, multisystem disease (especially diabetes), and alcohol abuse.…”

Farmacocinética das estatinas

“…Recentemente, foi mostrado que o gemfibrozil modula a farmacocinética das estatinas principalmente via inibição da glucuronidação e, como esperado, com pouca interferência na inibição do CYP3A4 18,19 . Estes aspectos mostram como uma interação ao nível de transporte pode afetar o metabolismo de estatinas que não compartilham uma mesma via de metabolização (como a interação gemfibrozil-pravastatina).…”